We propose to study a novel mechanism by which sensory neurons detect noxious stimuli. The ability to detect noxious stimuli is critical to survival, but can also be the source of unwanted pain. Injurious chemical, thermal and mechanical stimuli are transduced by a variety of G-protein coupled receptors and ion channels expressed in nociceptive sensory neurons. The signaling pathways in these neurons are undoubtedly complex, but deciphering these pathways promises the potential for improved treatment of pain-the most frequently cited health-care concern. One newly identified mode of noxious signaling occurs via the electrostatic charge of cations. Extracellular cations and polyamines can directly sensitize and gate the capsaicin receptor TRPV1, an ion channel essential for the development of inflammatory hyperalgesia. An important question arising from this observation is whether basic peptides can similarly modulate the function of TRPV1 and thereby regulate sensory nerve excitability. Immune and epithelial cells secrete an array of highly charged, cationic proteins and peptides. Importantly, levels of these cations are markedly elevated in inflamed tissue, however despite this observation;their effects on sensory nerve function have barely been explored. We hypothesize that polycations and cationic peptides can regulate the excitability of nociceptors through the modulation of TRPV1. We will test this innovative hypothesis using a combination of robust electrophysiological and biochemical methodologies: In Aim 1 we will determine the activation and sensitization of TRPV1 by several inflammatory cationic peptides/proteins. In Aim 2 we will explore the ability of polyamines and cationic peptides to trigger neuropeptide secretion from peripheral and central terminals of sensory nerve preparations. In Aim 3 we plan to identify nociceptive behaviors and pathology arising from cationic regulation of TRPV1.